The present invention relates to compounds that have biological activity with respect to estrogen receptors. The invention also relates to the use of such compounds to treat diseases and disorders related to estrogen receptor activity. More particularly, the present invention provides selective estrogen receptor modulators (“SERMs”) for use, for example, in treating mammalian cancers. The present invention therefore relates to the fields of medicine, medicinal chemistry, biochemistry, and endocrinology.
Estrogen is a hormone critical to normal human development and function. Although estrogen is the predominant “sex hormone” in women, in whom estrogen controls the development of female sex characteristics and the development and function of the reproductive system (Berkow, Beers et al. 1997), it is also found in men (Gustafsson 1998). Women produce estrogen primarily in the ovaries; however, estrogen affects a variety of physiological functions in women including body temperature regulation, maintenance of the vaginal lining, and preservation of bone density (Jordan 1998). In addition, estrogen provides additional effects that are related to its ability to modulate production of cholesterol in the liver, as demonstrated by the reduced occurrence of atherosclerosis in women compared to men due in part to the reduction of low-density lipoprotein (“LDL”) (Jordan 1998). Estrogen has also been implicated in delaying and/or reducing the severity of Alzheimer's Disease (Jordan 1998).
Failure to produce estrogen has profound physiological consequences in females. Failure to produce estrogen resulting from incomplete or absent ovary development (Turner's Syndrome) causes deficiencies in the skin, bone (e.g., severe osteoporosis), and other organs severely affecting the life of the afflicted individual (Dodge 1995). In normal women, estrogen production falls sharply upon the onset of menopause, usually at about 50 years of age. The effects of the loss of estrogen production include increased atherosclerotic deposits (leading to an increased incidence of heart disease), decreased bone density (osteoporosis), and fluctuations in body temperature (Jordan 1998). Often, the effects of reduced estrogen production are addressed by hormone replacement therapy (Dodge 1995; Berkow, Beers et al. 1997; Jordan 1998).
However, estrogen also has some undesirable side effects. In menopausal women, supplementation of estrogen is associated with alleviation of the above-described unwanted indications. But, administration of estrogen is also associated with increased risks for breast and endometrial cancer as well as blood clots (Jordan 1998). The increased risk of endometrial cancer can be addressed by the administration of progesterone (or its synthetic analog progestin) to re-initiate menstruation and thereby shed potentially malignant cells, but many older women find this undesirable (Jordan 1998). Breast cancer, however, is by far the greater risk of estrogen replacement therapy, affecting one woman in every 15 between the ages of 60 and 79 (Jordan 1998).
Estrogen has also been shown to function as a mitogen in estrogen-receptor positive breast cancer cells. Thus, treatment regiments which include antiestrogens, synthetic compounds which oppose, the actions of estrogen have been effective clinically in halting or delaying the progression of the disease (Jordan and Murphy, Endocrine Reviews 11:578-610 1990); Parker, Breast Cancer Res. Treat. 26:131-137 (1993)). The availability of these synthetic estrogen receptor modulators and subsequent dissection of their mechanism(s) of action have provided useful insights into estrogen receptor action.
The human estrogen receptor is a member of the nuclear receptor superfamily of transcription factors (Evans, Science 240:889-895 (1988)). In the absence of the hormone, it resides in the nucleus of target cells in a transcriptionally inactive state. Upon binding ligand, the estrogen receptor undergoes a conformational change initiating a cascade of events leading ultimately to its association with specific regulatory regions within target genes (O'Malley et al., Hormone Research 47:1-26 (1991)). The ensuing effect on transcription is influenced by the cell and promoter context of the DNA-bound receptor (Tora et al. Cell 59:471-487 (1989) (Tasset et al., Cell 62:1177-1181 (1990); McDonnell et all Mol. Endocrinol. 9:659-669 (1995); Tzukerman et al. Mol. Endocrinol. 8:21-30 (1994)). It is in this manner that the physiological estrogen receptor-agonist, estradiol, exerts its biological activity in the reproductive, skeletal and cardiovascular systems (Clark and Peck, Female Sex Steroids: Receptors and Function (eds) Monographs Springer-Verlag, New York (1979); Chow et al., J. Clin. Invest. 89:74-78 (1992); Eaker et al. Circulation 88:1999-2009 (1993)).
Thus, for a long time the treatment options for the serious health problems caused by a failure to produce estrogen were limited and entailed severe risks. However, the discovery that some agents acted as estrogen agonists in some tissues (e.g., bone) and as an antagonists in other tissues (e.g., breast) provided hope that more effective treatments for estrogen loss could be found (Gradishar and Jordan 1997; Gustafsson 1998; Jordan 1998; MacGregor and Jordan 1998).
Currently, the SERM's consist of two main chemical classes: the triphenylethylene derivatives and benzothiophene derivatives. SERM's approved by the Food and Drug Administration (FDA) and used in the treatment of breast cancer, are tamoxifen and toremifene. Another SERM, raloxifene is currently approved by the FDA for osteoporosis. Tamoxifen has been associated with endometrial cancer due to its estrogenic activity within the uterus while raloxifene lacks estrogenic activity within the uterus. However, tamoxifen has been associated with endometrial cancer and venous blood clots (Jordan 1998; MacGregor and Jordan 1998). In addition, tumor resistance to tamoxifen can occur (MacGregor and Jordan 1998).
It is apparent that there is a need to find a SERM with antiestrogenic activity and minimal side effects.
The best known of these so-called Selective Estrogen Receptor Modulators (“SERMs”), tamoxifen, has been demonstrated to have therapeutic utility in treating and preventing breast cancer and lowering LDL concentrations; yet, without significant reduction in bone density (Jordan 1998; MacGregor and Jordan 1998).
Estrogen is thought to be involved in the triggering of breast cancer as well as other cancers due to improper or excessive signaling. Tamoxifen as well as other SERMs are believed to block this triggering affect of estrogen. Over the years, tamoxifen has become the agent of choice in the treatment of all stages of breast cancer. Tamoxifen has provided an effective treatment against Estrogen receptor positive breast cancers. Clinical trials have shown that tamoxifen, when used as an adjuvant therapy, can increase the survival rate of women with estrogen receptor positive tumors and in women whose estrogen receptor status is not known. Nevertheless, tamoxifen is associated with serious side effects, such as thromboembolic events, negative vasomotor symptoms, and an increased risk of endometrial cancer and cataracts.
Tamoxifen has been followed recently by newer SERMs, in particular raloxifene, that promise to provide many of tamoxifen's benefits with fewer risks (Howell, Downey et al. 1996; Gradishar and Jordan 1997; Gustafsson 1998; Jordan 1998; Purdie 1999; Sato, Grese et al. 1999). These newer SERMs, including idoxifene (Nuttall, Bradbeer et al. 1998), CP-336, 156 (Ke, Paralkar et al. 1998), GW5638 (Willson, Norris et al. 1997), LY353581 (Sato, Turner et al. 1998) are part of the second and third generation of partial estrogen agonists/antagonists. In addition, a new generation of pure antiestrogens such as RU 58,688 (Van de Velde, Nique et al. 1994) have been reported. A large number of additional partial and pure estrogen agonist/antagonist compounds and treatment modalities have reported (Bryant and Dodge 1995; Bryant and Dodge 1995; Cullinan 1995; Dodge 1995; Grese 1995; Labrie and Merand 1995; Labrie and Merand 1995; Thompson 1995; Audia and Neubauer 1996; Black, Bryant et al. 1996; Thompson 1996; Cullinan 1997; Wilson 1997; Miller, Collini et al. 1999; Palkowitz 1999; Wilson 1999).
One embodiment of the present invention comprises a method of using aminoalkyloxy derivatives of 1,3,5(10)-Estratrien steroids as selective estrogen receptor modulators in the treatment of mammalian cancers. These compounds consist of various aminoalkyloxy derivatives of 1,3,5(10)-Estratrien steroids and are used, for example, as agents in the treatment of cancer in mammals. Selective estrogen receptor modulators (SERMs) are comprised of a group of compounds that act as estrogen receptor agonists in some tissues and as estrogen receptor antagonists in others. SERMs may interact with receptors, for example, by diffusing into the cell and binding to estrogen receptor subunits, α or β. During this process, there is a conformational change to the receptors which results in dimerization. It is this dimerization of receptors that facilitates binding to the promoter regions on DNA. The conformational change of receptors, particularly the position of helix 12, dictates whether the SERM is agonist or antagonist causing activation or suppression of estrogen target genes.
Toremifene is another FDA approved SERM used in the treatment of advanced breast cancer in postmenopausal women. Toremifene's efficacy is very similar to that of tamoxifen against estrogen positive metastatic breast cancer. In a worldwide phase III multi-center clinical trial comparing toremifene with tamoxifen, results indicated that the two drugs had very similar response rates of 44% for tamoxifen, 20 mg/day, while the response rates for toremifene were 50% and 48% at 60 and 200 mg/day, respectively. These results indicated that both drugs have similar efficacy in treating advanced breast cancer. As with tamoxifen, toremifene has also been studied as an adjuvant therapy. In this multi-center clinical trial, toremifene was not found to exhibit a statistically significant reduction in the recurrence of breast cancer. Surprisingly, toremifene has been associated with fewer side effects in comparison with tamoxifen. This advantage may be pivotal in the approval by the FDA as an adjuvant therapeutic treatment for breast cancer. Raloxifene is a SERM approved by the FDA in treatment and prevention of osteoporosis. Raloxifene has estrogen antagonist activity in breast tissue. Unfortunately, preclincal studies indicated that it has no advantage over tamoxifen in treating postmenopausal women with advanced breast cancer. In an addition, raloxifene is not effective against tamoxifen resistant breast cancer. But it is still being considered as a prophylactic therapy against cancer in high-risk women. Based upon the in vitro studies, the aminoalkyloxy derivatives of 1,3,5(10)-Estratrien steroids are effective at inhibiting the growth of cancer cells. Particularly, these derivatives are effective at inhibiting the growth of breast cancer cells such as MCF-7 cells. These same compounds may be effective against endometrial cancer cells.
Embodiments of the present invention provide aminoalkyloxy estrogen receptor agonist and antagonist compounds in addition to methods and compositions for treating or preventing estrogen receptor-mediated disorders. The compounds described herein have been found to have unexpected and surprising activity in modulating estrogen receptor activity. Thus, the compounds of the present invention may have utility in preventing or treating estrogen receptor-mediated disorders such as, for example, breast cancer, osteoporosis, endometrial cancers, atherosclerosis, menopause, premenstrual syndrome and Alzheimer's disease.
In a first aspect, the present invention provides compounds having the structure represented by:
or a stereoisomer, enantiomer, rotomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:a) R1 and R2 are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, andnitrogen to form a saturated 5 to 6 ring heterocycle,b) R3 is α or β methyl,c) n is an integer from 2 to 10,d) R4 is selected from the group consisting of hydrogen, hydroxy, ethynyl, fluorine, chlorine, bromine, iodine and acyloxy of a organic carboxylic acid of from 1 to 10 carbon atoms or taken together with the nitrogen to form a saturated 5 to 6 ring heterocycle optionally containing a second nitrogen or oxygen in the ring, carboxylic acid alkyl, alkenyl and alkynyl of from 1 to 10 carbons,e) R5 is selected from the group consisting of hydrogen, hydroxy, ethynyl, fluorine, chlorine, bromine, iodine and acyloxy of a organic carboxylic acid of from 1 to 10 carbon atoms or taken together with the nitrogen to form a saturated 5 to 6 ring heterocycle optionally containing a second nitrogen or oxygen in the ring, carboxylic acid alkyl, alkenyl and alkynyl of from 1 to 10 carbons, andf) R6 and R7 are independently selected from the group consisting of hydrogen, hydroxy, ethynyl, fluorine, chlorine, bromine, iodine and acyloxy of an organic carboxylic acid of from 1 to 10 carbons.
In yet another aspect, embodiments of the present invention provide methods for treating or preventing an estrogen receptor-mediated disorders in a mammalian subject in which an amount of an estrogen receptor-modulating compound of the invention that is effective to modulate estrogen receptor activity in the subject is administered. Other embodiments provide methods for treating a cell or an estrogen receptor-mediated disorder in a human or animal subject, comprising administering to the cell or to the human or animal subject an amount of a compound or composition of the invention embodiments effective to modulate estrogen receptor activity in the cell or subject. Representative estrogen receptor-mediated disorders include, for example, osteoporosis, atherosclerosis, estrogen-mediated cancers such as, for example, breast and endometrial cancer, and Alzheimer's disease.
These and other aspects and advantages will become apparent when the description below is read in conjunction with the accompanying examples and claims.